2-222201817-C-CA

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BA1

The NM_181458.4(PAX3):c.1420+126dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.239 in 127,078 control chromosomes in the GnomAD database, including 3,188 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.24 ( 3188 hom., cov: 24)

Exomes 𝑓: 0.28 ( 438 hom. )

Failed GnomAD Quality Control

Consequence

PAX3
NM_181458.4 intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: -0.474

Publications

3 publications found

Variant links:

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 Gene-Disease associations (from GenCC):

craniofacial-deafness-hand syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Waardenburg syndrome type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome type 3
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

PAX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 2-222201817-C-CA is Benign according to our data. Variant chr2-222201817-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334553.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.1420+126dupT		intron_variant	Intron 8 of 8	ENST00000392070.7	NP_852123.1	P23760-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 link	c.1420+126dupT		intron_variant	Intron 8 of 8	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

30384

AN:

127024

Hom.:

3182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.200

Gnomad AMI

AF:

0.199

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.281

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.250

Gnomad MID

AF:

0.327

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.228

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.275

AC:

329055

AN:

1194964

Hom.:

438

Cov.:

AF XY:

0.274

AC XY:

162486

AN XY:

593592

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.228

AC:

6055

AN:

26552

American (AMR)

AF:

0.188

AC:

6024

AN:

31962

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

6002

AN:

21596

East Asian (EAS)

AF:

0.263

AC:

8888

AN:

33786

South Asian (SAS)

AF:

0.273

AC:

19075

AN:

69778

European-Finnish (FIN)

AF:

0.243

AC:

9993

AN:

41156

Middle Eastern (MID)

AF:

0.263

AC:

948

AN:

3610

European-Non Finnish (NFE)

AF:

0.282

AC:

258333

AN:

916568

Other (OTH)

AF:

0.275

AC:

13737

AN:

49956

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.367

Heterozygous variant carriers

12324

24648

36972

49296

61620

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.239

AC:

30416

AN:

127078

Hom.:

3188

Cov.:

AF XY:

0.241

AC XY:

14723

AN XY:

61016

show subpopulations

African (AFR)

AF:

0.200

AC:

6808

AN:

34002

American (AMR)

AF:

0.224

AC:

2751

AN:

12302

Ashkenazi Jewish (ASJ)

AF:

0.281

AC:

864

AN:

3076

East Asian (EAS)

AF:

0.310

AC:

1400

AN:

4510

South Asian (SAS)

AF:

0.312

AC:

1260

AN:

4038

European-Finnish (FIN)

AF:

0.250

AC:

1920

AN:

7686

Middle Eastern (MID)

AF:

0.321

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.252

AC:

14786

AN:

58712

Other (OTH)

AF:

0.228

AC:

395

AN:

1736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1131

2262

3394

4525

5656

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0596

Hom.:

110

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Craniofacial-deafness-hand syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Waardenburg syndrome

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Aug 10, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-222201817-C-CA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over